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Modulating the Cellular Immune Response of Oligonucleotides by Brush Polymer-Assisted Compaction

Modulating the Cellular Immune Response of Oligonucleotides by Brush Polymer-Assisted Compaction
Xuyu Tan, Xueguang Lu, Xueyan Cao, Xiaoying Chen, Ke Zhang, Dali Wang, Fei Jia, Michelle Corley
Unwanted stimulation of the innate immune system by foreign nucleic acids has been one of the major barriers preventing bioactive sequences from reaching market. Foreign nucleic acids can be recognized by multiple pattern recognition receptors (PRRs), which trigger a signaling cascade to activate host defense systems, leading to a range of side effects. This study demonstrates that polyethylene glycol (PEG)-modified DNA strands can greatly reduce the activation of the innate immune system, and the extent of reduction is dependent upon polymer architecture. Highly branched brushes with long PEG side chains achieve the best suppression by blocking PRR interactions via a local steric effect. Interestingly, the brush polymer creates little barrier toward DNA–DNA interaction. Quantification of inflammatory cytokines in both mRNA and protein levels as well as the extent of cellular uptake shows a direct correlation between steric congestion and reduction of cellular immune response. These results suggest that the brush architecture offers unique advantages for PEGylating oligonucleotides in the context of minimizing unwanted immune system activation. A PEGylated DNA with brush polyethylene glycol architecture is developed to modulate the inflammatory response of oligonucleotide. The local steric effect on the brush polymer blocks pathogen recognition receptors from accessing the DNA, thus leading to a significant reduced immune response. This approach should drastically improve the immunogenicity of oligonucleotides and lead to their wider application as therapeutics.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/smll.201701432

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